Tumor necrosis factor (TNF-α) is an inflammatory cytokine produced by cells such as macrophages. It exhibits a variety of physiological activities, and thus is indispensable to protect the living body and maintain homeostasis. Meanwhile, overproduction of tumor necrosis factor (TNF-α) is considered to be responsible for allergic, inflammatory, or autoimmune diseases, such as chronic articular rheumatism, arthritis deformans, asthma, bronchitis, atopic dermatitis, inflammatory visceral disease, ulcerative colitis, Crohn's disease, and acquired immunological deficiency syndrome (AIDS), and thus compounds exhibiting TNF-α production inhibitory effect are expected to function as preventive or therapeutic remedies for these diseases.
Recent studies have reported that anti-TNF-α antibodies and soluble TNF-α receptors exhibit excellent clinical effect (Lancet 344 1105 (1994), Ann. Intern. Med. 130 478 (1999)), giving more solid grounds for the concept of anti-TNF-α therapy.
These antibodies and receptors are often called biological preparations, and injection is the unavoidable form for administering to a patient. Therefore, there remain needs for a low-molecular-weight compound which exhibits TNF-α production inhibitory effect and can be absorbed when administered via oral route.
Low-molecular-weight compounds heretofore disclosed to have TNF-α production inhibitory effect include oxyindole derivatives (WO 0122966, JP-A-2001-511449), thiazolyl derivatives (WO 0164674), pyrrole derivatives (JP-A-2001-181187, JP-A-2000-514808), piperidylpyrimidine derivatives (JP-A-2001-511764), picolinic acid derivatives (EP 926137), imidazopyridine derivatives (WO 0158900), tetrahydrothieno[2,3-c]pyridine derivatives (JP 13151779, JP 13158789, JP 13151780), and sulfonamide derivatives (WO 01/62751, WO 01/62715). However, none of these publications disclose specific information regarding absorption following oral administration.
Another compound; i.e., dihydropyridazinone derivative, has also been disclosed as having TNF-α production inhibitory effect (JP-A-2000-290261), but it greatly differs from the compounds of the present invention in terms of chemical structure.